BACKGROUND: Severe Graves\' disease is a life-changing condition with poor outcomes from currently available treatments. It is caused by directly pathogenic thyroid-stimulating hormone receptor-stimulating antibodies (TRAb), which are secreted from plasma cells. The human anti-CD38 monoclonal antibody daratumumab was developed to target plasma cells which express high levels of CD38, and is currently licensed for treatment of the plasma cell malignancy, myeloma. However, it can also deplete benign plasma cells with the potential to reduce TRAb and alter the natural history of severe Graves\' disease. This study aims to establish proof of concept that daratumumab has efficacy in patients with severe Graves\' disease and will provide important data to inform a choice of dosing regimen for subsequent trials.
METHODS: The Graves-PCD trial aims to determine if daratumumab modulates the humoral immune response in patients with severe Graves\' disease, and if so, over what time period, and to find an optimal dose. It is a single-blinded, randomised, dose-finding, adaptive trial using four different doses of daratumumab or placebo in 30 adult patients. Part 1 of the trial is dose-finding and, following an interim analysis, in part 2, the remaining patients will be randomised between the chosen dose(s) from the interim analysis or placebo. The primary outcome is the percentage change in serum TRAb from baseline to 12 weeks.
BACKGROUND: The trial received a favourable ethical opinion from London-Hampstead Research Ethics Committee (reference 21/LO/0449). The results of this trial will be disseminated at international meetings, in the peer-reviewed literature and through partner patient group newsletters and presentations at patient education events.
BACKGROUND: ISRCTN81162400.

BACKGROUND: Obexelimab is a bifunctional, non-cytolytic, humanised monoclonal antibody that binds CD19 and Fc gamma receptor IIb to inhibit B cells, plasmablasts, and CD19-expressing plasma cells. We aimed to evaluate the safety, clinical efficacy, and pharmacodynamic effects of obexelimab in patients with active IgG4-related disease.
METHODS: We conducted an open-label, single-arm, single centre, phase 2 pilot trial at the Massachusetts General Hospital in Boston, MA, USA. Eligible patients were aged 18-80 years and had active IgG4-related disease confirmed by an IgG4-related disease responder index score of 3 or more. Patients received 5 mg/kg of obexelimab intravenously every 2 weeks for 24 weeks. Patients on glucocorticoids at baseline were expected to discontinue usage within 2 months following enrolment. The primary endpoint was the proportion of patients with a decrease of 2 or more from baseline in the IgG4-related disease responder index at day 169 (ie, primary responders). Patients who achieved a decrease of 2 or more at any visit were designated as responders. Adverse events were graded on a scale of 1-5 (ie, mild, moderate, severe, life-threatening, or death) according to the Common Terminology Criteria for Adverse Events grading scale (version 4.3). Exploratory analyses were quantification of B-cell CD19 receptor occupancy, plasmablast, total B-cell and CD4+ cytotoxic T-cell count by flow cytometry, and immunoglobulin concentrations by nephelometry. This study is registered with ClinicalTrials.gov, NCT02725476.
RESULTS: Between Feb 24, 2016, and Dec 21, 2016, we enrolled 15 patients. The median age was 63 years (IQR 52-65). Ten (67%) of 15 patients were male, five (33%) were female, and 12 (80%) were White. At baseline, 12 (80%) of 15 patients had an elevated median serum IgG4 concentration of 220 mg/dL (IQR 124-441), and the median IgG4-related disease responder index score was 12 (IQR 7-13). 12 (80%) of 15 patients achieved the primary endpoint (ie, primary responders), 14 (93%) were defined as responders. Reductions from baseline in serum B cells and plasmablasts were observed following treatment with obexelimab. However, in most patients with follow-up data, serum B cells recovered to 75% of baseline concentrations within 42 days of the final obexelimab dose. 13 (87%) of 15 patients reported adverse events, one of which (an infusion reaction) resulted in treatment discontinuation.
CONCLUSIONS: All patients except for one had clinical responses to obexelimab treatment. Both reductions in circulating B cells without evidence of apoptosis during obexelimab treatment and their rapid rebound after treatment discontinuation suggest that obexelimab might lead to B-cell sequestration in lymphoid organs or the bone marrow. These results support the continued development of obexelimab for the treatment of IgG4-related disease.
BACKGROUND: Xencor, Zenas BioPharma, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute of Allergy and Infectious Diseases.

OBJECTIVE: DnaJ homolog subfamily B member 9 (DNAJB9) is a co-chaperone protein that governs the functions and integrity of cells. In immunoglobulin G4-related disease (IgG4-RD), DNAJB9 was shown to be upregulated in plasma cells, but its immunohistochemical expression has never been explored. This pilot study aims to investigate the immunohistochemical distribution and intensity of DNAJB9 in IgG4-RD tissue specimens.
METHODS: Patients with definite IgG4-RD and normal tissue controls were selected for anti-DNAJB9 immunohistochemistry, applying a semi-quantitative staining intensity score.
RESULTS: We studied the tissue slides of 9 IgG4-RD patients and 15 controls, including salivary gland, pancreatic, pulmonary, pleural, and retroperitoneal fibrosis tissue. Median immunohistochemical intensity was 0 for IgG4-RD patients vs. 2 for controls for endothelial cells (ES=1.58, p<0.01), 2 in each group for glandular epithelial cells (ES 0.70, p=0.26), and 2 for IgG4-RD vs. 3 for controls for inflammatory cells regarding salivary glands alone (ES=0.90, p=0.11). Endothelial staining intensity was negatively correlated with serum IgG4 concentrations (r= -0.72, p=0.03) and the number of treatments required to achieve disease remission (r= -0.70, p=0.04).
CONCLUSIONS: Our findings evidenced reduced immunohistochemical expression of DNAJB9 in IgG4-RD endothelial cells, and suggested loss of expression in other cell types, possibly correlating with disease severity and risk of relapse. Although DNAJB9 may not serve as a marker for IgG4-RD, it may be part of a pathophysiological pathway involved in the disease and the onset of fibrosis.

Monoclonal gammopathy of undetermined significance (MGUS) is the earliest discernible stage of multiple myeloma (MM) and Waldenström\'s macroglobulinemia (WM). Early diagnosis of MG may be compromised by the low-level infiltration, undetectable to low-sensitive methodologies. Here, we investigated the prevalence and immunophenotypic profile of clonal (c) plasma cells (PC) and/or cB-lymphocytes in bone marrow (BM) and blood of subjects with a serum M-component from the iSTOPMM program, using high-sensitive next-generation flow cytometry (NGF), and its utility in the diagnostic classification of early-stage MG. We studied 164 paired BM and blood samples from 82 subjects, focusing the analysis on: 55 MGUS, 12 smoldering MM (SMM) and 8 smoldering WM (SWM). cPC were detected in 84% of the BM samples and cB-lymphocytes in 45%, coexisting in 39% of cases. In 29% of patients, the phenotypic features of cPC and/or cB-lymphocytes allowed a more accurate disease classification, including: 19/55 (35%) MGUS, 1/12 (8%) SMM and 2/8 (25%) SWM. Blood samples were informative in 49% of the BM-positive cases. We demonstrated the utility of NGF for a more accurate diagnostic classification of early-stage MG.

Hidradenitis suppurativa (HS) is an autoinflammatory disorder of keratinization with a prominence of B cells and plasma cells. Fostamatinib is a spleen tyrosine kinase inhibitor targeting B cells and plasma cells.
To assess the safety, tolerability, and clinical response at week 4 and week 12 of fostamatinib in moderate-to-severe HS.
Twenty participants were administered fostamatinib 100 mg twice a day for 4 weeks, escalating to 150 mg twice a day thereafter until week 12. Participants were assessed for adverse events and clinical response assessed by HiSCR (Hidradenitis Suppurativa Clinical Response Score) and IHS4 (International Hidradenitis Suppurativa Severity Score) as well as other outcomes including DLQI (Dermatology Life Quality Index), visual analog scale, and physician global assessment.
All 20 participants completed the week 4 and week 12 endpoints. Fostamatinib was well tolerated in this cohort with no grade 2/3 adverse events reported. A total of 85% achieved HiSCR at week 4 and 85% at week 12. The greatest reduction in disease activity was seen at weeks 4/5 with worsening in a proportion of patients thereafter. Significant improvements were seen in pain, itch, and quality of life.
Fostamatinib was well tolerated in this HS cohort with no serious adverse events and improvement in clinical outcomes. Targeting B cells/plasma cells may be a viable therapeutic strategy in HS and requires further exploration.

BACKGROUND: Autoimmune hepatitis (AIH) is associated with periportal infiltration by plasma cells. Plasma cell detection is routinely performed through hematoxylin and eosin (H&E) staining. The present study aimed to assess the utility of CD138, an immunohistochemical plasma cell marker, in the evaluation of AIH.
METHODS: A retrospective study was conducted, in which cases consistent with AIH, within the time frame of 2001 and 2011, were collected. Routine H&E-stained sections were used for evaluation. CD138 immunohistochemistry (IHC) was performed to detect plasma cells.
RESULTS: Sixty biopsies were included. In the H&E group, the median and interquartile range (IQR) was 6 (4-9) plasma cells/high power field (HPF) and was 10 (IQR 6-20) plasma cells/HPF in the CD138 group (p < 0.001). There was a significant correlation between the number of plasma cells determined by H&E and CD138 (p = 0.31, p = 0.01). No significant correlation was found between the number of plasma cells determined by CD138 and IgG level (p = 0.21, p = 0.09) or stage of fibrosis (p = 0.12, p = 0.35), or between IgG level and stage of fibrosis (p = 0.17, p = 0.17). No significant correlation was found between the treatment response and the number of plasma cells determined by H&E (p = 0.11, p = 0.38), CD138 (p = 0.07, p = 0.55), or stage of fibrosis (p = 0.16, p = 0.20). CD138 expression was different between the treatment response groups (p = 0.04).
CONCLUSIONS: CD138 increased the detection of plasma cells in liver biopsies of patients with AIH, when compared with routine H&E staining. However, there was no correlation between the number of plasma cells determined by CD138 and serum IgG levels, stage of fibrosis, or response to treatment.

Plasma cell mastitis (PCM) is a nonbacterial breast inflammation with severe and intense clinical manifestation, yet treatment methods for PCM are still rather limited. Although the mechanism of PCM remains unclear, mounting evidence suggests that the dysregulation of immune system is closely associated with the pathogenesis of PCM. Drug combinations or combination therapy could exert improved efficacy and reduced toxicity by hitting multiple discrete cellular targets.
We have developed a knowledge graph architecture toward immunotherapy and systematic immunity that consists of herbal drug-target interactions with a novel scoring system to select drug combinations based on target-hitting rates and phenotype relativeness. To this end, we employed this knowledge graph to identify an herbal drug combination for PCM and we subsequently evaluated the efficacy of the herbal drug combination in clinical trial.
Our clinical data suggests that the herbal drug combination could significantly reduce the serum level of various inflammatory cytokines, downregulate serum IgA and IgG level, reduce the recurrence rate, and reverse the clinical symptoms of PCM patients with improvements in general health status.
In summary, we reported that an herbal drug combination identified by knowledge graph can alleviate the clinical symptoms of PCM patients. We demonstrated that the herbal drug combination holds great promise as an effective remedy for PCM, acting through the regulation of immunoinflammatory pathways and improvement of systematic immune level. In particular, the herbal drug combination could significantly reduce the recurrence rate of PCM, a major obstacle to PCM treatment. Our data suggests that the herbal drug combination is expected to feature prominently in future PCM treatment.
C. Liu\'s lab was supported by grants from the Public Health Science and Technology Project of Shenyang (grant: 22-321-32-18); Y. Yang\'s laboratory was supported by the National Natural Science Foundation of China (grant: 81874301), the Fundamental Research Funds for Central University (grant: DUT22YG122), and the Key Research project of \'be Recruited and be in Command\' in Liaoning Province (2021JH1/10400050).
NCT05530226.

OBJECTIVE: Plasma cell vulvitis (PCV) is a rare inflammatory vulvar condition. The aim of this study was to describe the natural history, treatment, impact on quality of life, and factors associated with poorer outcomes for PCV.
METHODS: A mixed-methods approach was used combining a retrospective case note review with a cross-sectional telephone questionnaire. All women diagnosed with PCV attending the vulvar disorders clinic at the Royal Women\'s Hospital between January 2011 and December 2020 were included.
RESULTS: During the 10-year study period, 7,500 women were seen at the vulval disorders clinic, of whom 21 were diagnosed with PCV (0.28%). Of these women, 12 who were followed up for more than 12 months agreed to participate in the study. At a median of 5 years follow-up, there was variability in symptom severity, with more than half of the women still symptomatic with pain, precipitated by friction and dyspareunia, resulting in a moderate to large impact on quality of life. There were 5 women who were asymptomatic. Only 1 woman had a preexisting history of lichen planus and lichen sclerosus. Potent topical corticosteroids were identified as the preferred treatment.
CONCLUSIONS: Women with PCV can remain symptomatic for many years with significant impacts on quality of life, which may consequently require long-term support and follow-up.

OBJECTIVE: Based on the modified diagnostic criteria for oral lichen planus (OLP) proposed by Van der Meij and Van der Waal, the objective of the current investigation was to demonstrate a clinicohistopathological association in the diagnosis of OLP.
METHODS: Data were retrieved from 250 individuals who visited the Department of Oral Medicine and Radiology and were diagnosed with OLP between September 2018 and December 2021. Upon completion of the histopathological analysis, the precise diagnosis of OLP was made. Repeat biopsies were performed in the cases suspecting malignant transformation during the follow-up phase. The data were analyzed using SPSS software. The Fisher\'s exact test and chi-square test of association were used to establish the significant differences between the variables at a 5% significance level.
RESULTS: Of the 250 patients, 48% and 52% were males and females, respectively. The two clinical manifestations observed were reticular (n=145, 58%) and erosive types (n=105, 42%). The most frequently impacted locations were the buccal mucosa (n=150, 60%) and labial mucosa (n=100, 40%). Fourteen individuals (two with reticular form and 12 with erosive form) later during follow-up showed dysplasia, with moderate (n=2) to mild (n=12) dysplastic alterations. Koilocytes were reported in 84 cases (34%), which included 35 (24%) reticular cases and 49 (47%) erosive lesions. The histopathological features such as acanthosis, epithelial atrophy, hyperkeratosis, presence of neutrophils, koilocytes, and epithelial dysplasia were shown to be statistically significant between the clinical forms (p<0.001).
CONCLUSIONS: The results of the current study highlight the concordance of histopathological and clinical diagnoses, especially for early definitive diagnosis of OLP. More research studies are warranted to validate the trend of epithelial dysplasia in OLP associated with human papillomavirus (HPV) and to explore the course of the lesions that might be affected by this trait.

Despite the extensive number of publications in the field of radiomics, radiomics algorithms barely enter large-scale clinical application. Supposedly, the low external generalizability of radiomics models is one of the main reasons, which hinders the translation from research to clinical application. The objectives of this study were to investigate reproducibility of radiomics features (RFs) in vivo under variation of patient positioning, magnetic resonance imaging (MRI) sequence, and MRI scanners, and to identify a subgroup of RFs that shows acceptable reproducibility across all different acquisition scenarios.
Between November 30, 2020 and February 16, 2021, 55 patients with monoclonal plasma cell disorders were included in this prospective, bi-institutional, single-vendor study. Participants underwent one reference scan at a 1.5 T MRI scanner and several retest scans: once after simple repositioning, once with a second MRI protocol, once at another 1.5 T scanner, and once at a 3 T scanner. Radiomics feature from the bone marrow of the left hip bone were extracted, both from original scans and after different image normalizations. Intraclass correlation coefficient (ICC) was used to assess RF repeatability and reproducibility.
Fifty-five participants (mean age, 59 ± 7 years; 36 men) were enrolled. For T1-weighted images after muscle normalization, in the simple test-retest experiment, 110 (37%) of 295 RFs showed an ICC ≥0.8: 54 (61%) of 89 first-order features (FOFs), 35 (95%) of 37 volume and shape features, and 21 (12%) of 169 texture features (TFs). When the retest was performed with different technical settings, even after muscle normalization, the number of FOF/TF with an ICC ≥0.8 declined to 58/13 for the second protocol, 29/7 for the second 1.5 T scanner, and 49/7 for the 3 T scanner, respectively. Twenty-five (28%) of the 89 FOFs and 6 (4%) of the 169 TFs from muscle-normalized T1-weighted images showed an ICC ≥0.8 throughout all repeatability and reproducibility experiments.
In vivo, only few RFs are reproducible with different MRI sequences or different MRI scanners, even after application of a simple image normalization. Radiomics features selected by a repeatability experiment only are not necessarily suited to build radiomics models for multicenter clinical application. This study isolated a subset of RFs, which are robust to variations in MRI acquisition observed in scanners from 1 vendor, and therefore are candidates to build reproducible radiomics models for monoclonal plasma cell disorders for multicentric applications, at least when centers are equipped with scanners from this vendor.